CN110467586A - A kind of preparation method of flunarizine hydrochloride crystallization - Google Patents
A kind of preparation method of flunarizine hydrochloride crystallization Download PDFInfo
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- CN110467586A CN110467586A CN201910820519.7A CN201910820519A CN110467586A CN 110467586 A CN110467586 A CN 110467586A CN 201910820519 A CN201910820519 A CN 201910820519A CN 110467586 A CN110467586 A CN 110467586A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/06—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by halogen atoms or nitro radicals
- C07D295/073—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by halogen atoms or nitro radicals with the ring nitrogen atoms and the substituents separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
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Abstract
The present invention relates to a kind of crystallization preparation methods of flunarizine hydrochloride.Flunarizine hydrochloride, is added in the aqueous solution of low boiling point organic solvent by the flunarizine hydrochloride crystallization preparation method that granularity of the present invention is 20~30 microns first；It is evaporated under reduced pressure, temperature is 50 ~ 80 DEG C, vacuum degree is 0.03 ~ 0.08MPa, partial solvent is steamed by the evaporation rate of 10% ~ 25%/hour of solvent total amount of evaporation rate, after crystal precipitation, growing the grain 30~60 minutes, it then proceedes to be evaporated under reduced pressure, when distillate volume is the 30 ~ 65% of solvent volume, stop evaporation, growing the grain；5 ~ 10 DEG C are cooled to 5 ~ 10 DEG C/h of cooling rate, and maintains this temperature growing the grain 30~60 minutes；Filtering, and filter cake is washed with solvent.The present invention provides a kind of flunarizine hydrochloride crystallization preparation methods that granularity is controllable.
Description
Technical field
The present invention relates to a kind of preparation methods of flunarizine hydrochloride crystallization, belong to crystallization technique field.
Background technique
With being constantly progressive for pharmaceutical industry technology, the micromeritis quality index of more and more research discovery drugs is shadow
Ring one of the key factor of oral solid formulation product development and quality control.Granule size and its distribution are used as medicament powder
An important indicator in matter, not only will affect the apparent condition of drug, but also will have a direct impact on and be filtered, washed, dries and waited
The production efficiency of journey, but will the indexs such as rate of dissolution, uniformity of dosage units, stability to drug generate considerable influence.
Flunarizine hydrochloride (Flunarizine Hydrochloride), entitled (E) -1- [double-(the 4- fluorophenyl) of chemistry
Methyl] -4-(2- acrylic -3- phenyl) piperazine dihydrochloride, molecular formula C26H26F2N22HCl, molecular weight is
477.42, No. CAS is 30484-77-6, for white or off-white color crystallization or crystalline powder powder；It is odorless.In methanol or second
Slightly molten in alcohol, the slightly soluble in chloroform, soluble,very slightly, almost insoluble in benzene in water.Its chemical structural formula such as following formula institute
Show:
。
For flunarizine hydrochloride as calcium channel blocker, intracelluar rationality calcium caused by capable of preventing because of factors such as ischemics is super
Carry and caused by cell damage.Suitable for cerebral arteriovenous malformation, cerebral thrombosis, cerebral embolism, the disturbance of cerebral circulation of caused by hypertension,
Cerebral hemorrhage, disturbance of cerebral circulation caused by arachnoid, cerebral hemorrhage etc..The product was synthesized by Janssen in 1970 for the first time, by one
The clinical test of series, takes the lead in listing in Europe, then lists in 1989 in China.Prophylactic treatment of the medicine in migraines
With the symptomatic treatment field of the dizziness as caused by first front yard dysfunction, significant curative effect is achieved, the support by vast sufferer
With welcome, global marketing volume is risen year by year, and economic and social benefit is significant.
The former lapping compound type of flunarizine hydrochloride is capsule, mostly use in production process it is directly filling, to hydrochloric acid fluorine osmanthus benefit
The mobility of piperazine has high requirement.However, the flunarizine hydrochloride appearance that traditional handicraft obtains is in elongated aciculiform (such as attached drawing 1
It is shown), it easily coalesces, causes overall flow poor, certain difficulty is caused to preparation production.Formulation process is adopted more
Long acicular flunarizine hydrochloride is crushed with gas flow crushing process, to guarantee its mobility, not only energy consumption is high for process, material damage
Mistake is more, also causes certain dust pollution.The work of drug Conformance Assessment proves, when the granularity of flunarizine hydrochloride is 20~30
When micron, the outer dissolved corrosion of prepared capsule body is consistent.Currently, without document report how by way of crystallization preparative
Can stable, good fluidity flunarizine hydrochloride bulk pharmaceutical chemicals product, to the powder properties of flunarizine hydrochloride bulk pharmaceutical chemicals (such as grain
Degree distribution, mobility etc.) regulation still belong to blank area.How to obtain size distribution is uniform, good fluidity hydrochloric acid fluorine osmanthus benefit
Piperazine is a great problem in current industry, needs to be resolved.
Summary of the invention
Goal of the invention: providing a kind of crystallization preparation method of flunarizine hydrochloride, the hydrochloric acid fluorine osmanthus prepared using this method
Sharp piperazine product appearance is in bulk, and even particle size distribution, without crushing, powder flowing performance is good.
The present invention be obtain without crushing, powder flowing performance is good and the production of the blocky flunarizine hydrochloride of even particle size distribution
Product have carried out system research to its crystallization processes, and the flunarizine hydrochloride for finally obtaining main granularity between 20~30 microns crystallizes
Product, not only powder flowing performance is good, and granularity is in normal distribution, and the hydrochloric acid fluorine osmanthus that dissolved corrosion and traditional handicraft obtain
Sharp piperazine product is similar.
Technical solution
The technical scheme is that
A kind of crystallization preparation method of the flunarizine hydrochloride of main granularity between 20~30 microns, comprising the following steps:
Flunarizine hydrochloride is added in the aqueous solution of low boiling point organic solvent by the first step, and the liquid-solid ratio of solution is 10 mL/g
~53 mL/g continuously stir dissolution 30~60 minutes at 50~80 DEG C, decolourize, filtering；The low boiling point organic solvent choosing
From one of methanol, ethyl alcohol, isopropanol, acetone, acetonitrile.
Preferably, in the aqueous solution of the low boiling point organic solvent, water in the mixed solvent volume fraction be 2%~
20%。
Preferably, the solid-to-liquid ratio of the solution is the mL/g of 10 mL/g~30.
Preferably, the low boiling point organic solvent is selected from one of methanol, ethyl alcohol, isopropanol, and water is in mixed solvent
In volume fraction be 5%~15%.
Filtrate obtained by the first step is evaporated under reduced pressure in second step, and the temperature of reduction vaporization is 50 ~ 80 DEG C, and vacuum degree is 0.03 ~
0.08MPa steams partial solvent by the evaporation rate of 10% ~ 25%/hour of solvent total amount of evaporation rate, is precipitated to crystal
Afterwards, stop evaporation, growing the grain 30~60 minutes, continue to be evaporated under reduced pressure with evaporation rate as before, when distillate volume is molten
Agent volume 30 ~ 65% when, stop evaporation, growing the grain 30 ~ 120 minutes.
Preferably, the reduction vaporization rate is that steam part molten for the evaporation rate of 15% ~ 20%/hour of solvent total amount
Agent.
System obtained by second step is cooled to 5 ~ 10 DEG C with 5 ~ 10 DEG C/h of cooling rate by third step, and maintains this temperature
Degree growing the grain 30~60 minutes.
Preferably, growing the grain temperature is 6-8 DEG C.
The filtering of 4th step, and filter cake is washed with solvent.40~80 DEG C of dryings of filter cake, obtain even particle size distribution, powder flow
The excellent flunarizine hydrochloride product of dynamic property, the cleaning solvent are one of methanol, ethyl alcohol, isopropanol, acetone, acetonitrile.
Drying time 8~12 hours described in 4th step.
The utility model has the advantages that
The present invention provides a kind of flunarizine hydrochloride crystallization preparation method that granularity is controllable, product HPLC content reaches
99.90% or more, stability test proves that room temperature is stored 6 months, and without clustering phenomena between crystal, main granularity is micro- between 20~30
Rice, even particle size distribution, powder fluidity is excellent, and the one way molar yield of crystallization process is suitble to industry metaplasia 85.0% or more
It produces.Flunarizine hydrochloride crystal provided by the invention, complete crystal form, epigranular and controllable magma are easily filtered, washed and do
Dry, the labor intensity of technological operation is low.
Detailed description of the invention
Fig. 1: the microscope photo (200 times of amplification) of traditional handicraft flunarizine hydrochloride product；
Fig. 2: the microphoto (100 times of amplification) of embodiment 1-7 flunarizine hydrochloride product；
Fig. 3: the particle size distribution figure of embodiment 1-7 flunarizine hydrochloride product.
Specific embodiment
Flunarizine hydrochloride of the embodiment of the present invention is same batch, by prior art preparation, purity 99.2%.
Embodiment 1
20g flunarizine hydrochloride is added and fills the three of 200mL methanol and water mixed solvent (methanol is 90:10 with water volume ratio)
In mouth bottle, it is warming up to 50 DEG C of stirring dissolved clarifications.Active carbon decoloring, filtering are added later；Filtrate is transferred in 50 DEG C of crystallizers, is started
Evaporative crystallization, for control system vacuum degree in 0.03MPa, evaporation rate is 30mL/ hours, after having crystal precipitation in crystallizer,
Stop evaporation, insulated and stirred growing the grain 30min continues evaporative crystallization later, stops evaporation when steaming solvent total amount and reaching 60mL.
Insulated and stirred growing the grain 30min is cooled to 5 DEG C later with 5 DEG C/h of cooling rate stirring, insulated and stirred 1h.It filters, is used in combination
Methanol elute filter cake, 40 DEG C constant pressure and dry 8 hours, obtain 18.06g bulk flunarizine hydrochloride product (as shown in Fig. 1), receipts
Rate 90.3%, HPLC purity 99.92%, 24.055 μm of main granularity of product (as shown in Fig. 2).
Embodiment 2
20g flunarizine hydrochloride is added and fills the three of 300mL ethyl alcohol and water mixed solvent (ethyl alcohol is 95:5 with water volume ratio)
In mouth bottle, it is warming up to 65 DEG C of stirring dissolved clarifications.Active carbon decoloring, filtering are added later；Filtrate is transferred in 65 DEG C of crystallizers, is started
Evaporative crystallization, for control system vacuum degree in 0.05MPa, evaporation rate is 50mL/ hours, after having crystal precipitation in crystallizer,
Stop evaporation, insulated and stirred growing the grain 45min continues evaporative crystallization later, stops steaming when steaming solvent total amount and reaching 195mL
Hair.Insulated and stirred growing the grain 120min is cooled to 8 DEG C later with 6 DEG C/h of cooling rate stirring, insulated and stirred 45min.It takes out
Filter, and with ethanol rinse filter cake, 60 DEG C constant pressure and dry 10 hours, obtain 18.27g bulk flunarizine hydrochloride product, yield
91.35%, HPLC purity 99.94%, 26.588 μm of the main granularity of product.
Embodiment 3
20g flunarizine hydrochloride is added and fills the three of 400mL ethyl alcohol and water mixed solvent (ethyl alcohol is 85:15 with water volume ratio)
In mouth bottle, it is warming up to 50 DEG C of stirring dissolved clarifications.Active carbon decoloring, filtering are added later；Filtrate is transferred in 65 DEG C of crystallizers, is started
Evaporative crystallization, for control system vacuum degree in 0.04MPa, evaporation rate is 60mL/ hours, after having crystal precipitation in crystallizer,
Stop evaporation, insulated and stirred growing the grain 45min continues evaporative crystallization later, stops steaming when steaming solvent total amount and reaching 200mL
Hair.Insulated and stirred growing the grain 100min is cooled to 5 DEG C later with 5 DEG C/h of cooling rate stirring, insulated and stirred 45min.It takes out
Filter, and with ethanol rinse filter cake, 60 DEG C constant pressure and dry 12 hours, obtain 18.06g bulk flunarizine hydrochloride product, yield
90.3%, HPLC purity 99.92%, 20.403 μm of the main granularity of product.
Embodiment 4
The addition of 10g flunarizine hydrochloride is filled into 500mL isopropanol and water mixed solvent (isopropanol is 93:7 with water volume ratio)
There-necked flask in, be warming up to 80 DEG C of stirring dissolved clarifications.Active carbon decoloring, filtering are added later；Filtrate is transferred in 80 DEG C of crystallizers,
Starting evaporative crystallization, for control vacuum degree in 0.08MPa, evaporation rate is 100mL/ hours, after having crystal precipitation in crystallizer,
Stop evaporation, insulated and stirred growing the grain 60min continues evaporative crystallization later, stops steaming when steaming solvent total amount and reaching 250mL
Hair.Insulated and stirred growing the grain 60min is cooled to 8 DEG C later with 10 DEG C/h of cooling rate stirring, insulated and stirred 30min.It takes out
Filter, and with isopropanol elute filter cake, 80 DEG C constant pressure and dry 10 hours, obtain 9.23g bulk flunarizine hydrochloride product, yield
92.3%, HPLC purity 99.91%, 29.874 μm of the main granularity of product.
Embodiment 5
20g flunarizine hydrochloride is added and fills the three of 400mL acetone and water mixed solvent (acetone is 80:20 with water volume ratio)
In mouth bottle, it is warming up to 50 DEG C of stirring dissolved clarifications.Active carbon decoloring, filtering are added later；Filtrate is transferred in 50 DEG C of crystallizers, is started
Evaporative crystallization, for control vacuum degree in 0.06MPa, evaporation rate is 40mL/ hours, after having crystal precipitation in crystallizer, is stopped
Evaporation, insulated and stirred growing the grain 50min continue evaporative crystallization later, stop evaporation when steaming solvent total amount and reaching 160mL.It protects
Temperature stirring growing the grain 100min is cooled to 5 DEG C later with 8 DEG C/h of cooling rate stirring, insulated and stirred 40min.It filters, and
Elute filter cake with acetone, 50 DEG C constant pressure and dry 8 hours, obtain 17.71g bulk flunarizine hydrochloride product, yield 88.55%,
HPLC purity 99.93%, 28.724 μm of the main granularity of product.
Embodiment 6
20g flunarizine hydrochloride is added and fills the three of 800mL acetonitrile and water mixed solvent (acetonitrile is 98:2 with water volume ratio)
In mouth bottle, it is warming up to 70 DEG C of stirring dissolved clarifications.Active carbon decoloring, filtering are added later；Filtrate is transferred in 70 DEG C of crystallizers, is started
Evaporative crystallization, for control vacuum degree in 0.08MPa, evaporation rate is 150mL/ hours, after having crystal precipitation in crystallizer, is stopped
Evaporation, insulated and stirred growing the grain 60min continue evaporative crystallization later, stop evaporation when steaming solvent total amount and reaching 400mL.It protects
Temperature stirring growing the grain 90min is cooled to 10 DEG C later with 10 DEG C/h of cooling rate stirring, insulated and stirred 60min.It filters, and
Elute filter cake with acetonitrile, 65 DEG C constant pressure and dry 10 hours, obtain 17.48g bulk flunarizine hydrochloride product, yield 87.4%,
HPLC purity 99.90%, 24.649 μm of the main granularity of product.
Embodiment 7
15g flunarizine hydrochloride is added and fills the three of 800mL acetonitrile and water mixed solvent (acetonitrile is 95:5 with water volume ratio)
In mouth bottle, it is warming up to 65 DEG C of stirring dissolved clarifications.Active carbon decoloring, filtering are added later；Filtrate is transferred in 65 DEG C of crystallizers, is started
Evaporative crystallization, for control vacuum degree in 0.08MPa, evaporation rate is 200mL/ hours, after having crystal precipitation in crystallizer, is stopped
Evaporation, insulated and stirred growing the grain 60min continue evaporative crystallization later, stop evaporation when steaming solvent total amount and reaching 300mL.It protects
Temperature stirring growing the grain 60min is cooled to 5 DEG C later with 10 DEG C/h of cooling rate stirring, insulated and stirred 30min.It filters, and
With acetonitrile elute filter cake, 65 DEG C constant pressure and dry 9 hours, obtain 12.8g bulk flunarizine hydrochloride product, yield 85.3%, HPLC
Purity 99.92%, 28.054 μm of the main granularity of product.
The flunarizine hydrochloride crystallization preparation method that the present invention is disclosed and proposed, those skilled in the art can be by using for reference this
Literary content, the links such as appropriate feed change, technological parameter are realized.Method of the invention and product passed through preferred embodiment into
Gone description, related technical personnel obviously can not depart from the content of present invention, in spirit and scope to method described herein and
Product is modified or appropriate changes and combinations, Lai Shixian the technology of the present invention.In particular, it should be pointed out that all similar replaces
Change and change it is apparent to those skilled in the art, they be considered as being included in spirit of that invention, range and
In content.
Claims (7)
1. a kind of crystallization preparation method of flunarizine hydrochloride of main granularity between 20~30 microns, which is characterized in that including with
Lower step:
Flunarizine hydrochloride is added in the aqueous solution of low boiling point organic solvent by the first step, and the liquid-solid ratio of solution is 10 mL/g
~53 mL/g continuously stir dissolution 30~60 minutes at 50~80 DEG C, decolourize, filtering；The low boiling point organic solvent choosing
From one of methanol, ethyl alcohol, isopropanol, acetone, acetonitrile；
Filtrate obtained by the first step is evaporated under reduced pressure in second step, and the temperature of reduction vaporization is 50 ~ 80 DEG C, and vacuum degree is 0.03 ~
0.08MPa steams partial solvent by the evaporation rate of 10% ~ 25%/hour of solvent total amount of evaporation rate, is precipitated to crystal
Afterwards, stop evaporation, growing the grain 30~60 minutes, then proceed to be evaporated under reduced pressure, when distillate volume is the 30 ~ 65% of solvent volume,
Stop evaporating, growing the grain 30 ~ 120 minutes；
System obtained by second step is cooled to 5 ~ 10 DEG C with 5 ~ 10 DEG C/h of cooling rate by third step, and this temperature is maintained to support
It is 30~60 minutes brilliant；
The filtering of 4th step, and filter cake is washed with solvent, 40~80 DEG C of dryings of filter cake obtain flunarizine hydrochloride product of the present invention, institute
Stating cleaning solvent is one of methanol, ethyl alcohol, isopropanol, acetone, acetonitrile.
2. crystallization preparation method of the main granularity between 20~30 microns of flunarizine hydrochloride according to claim 1, spy
Sign is, in the aqueous solution of low boiling point organic solvent described in the first step, water in the mixed solvent volume fraction be 2%~
20%。
3. crystallization preparation method of the main granularity between 20~30 microns of flunarizine hydrochloride according to claim 1, spy
Sign is that the solid-to-liquid ratio of flunarizine hydrochloride solution obtained by the first step is the mL/g of 10 mL/g~30.
4. crystallization preparation method of the main granularity between 20~30 microns of flunarizine hydrochloride according to claim 1, spy
Sign is that low boiling point organic solvent described in the first step is selected from one of methanol, ethyl alcohol, isopropanol.
5. crystallization preparation method of the main granularity between 20~30 microns of flunarizine hydrochloride according to claim 1, spy
Sign is that low boiling point organic solvent described in the first step is selected from one of methanol, ethyl alcohol, isopropanol, and water is in the mixed solvent
Volume fraction be 5%~15%.
6. crystallization preparation method of the main granularity between 20~30 microns of flunarizine hydrochloride according to claim 1, spy
Sign is, it is molten that reduction vaporization rate described in second step is that the evaporation rate of 15% ~ 20%/hour of solvent total amount steams part
Agent.
7. crystallization preparation method of the main granularity between 20~30 microns of flunarizine hydrochloride according to claim 1, spy
Sign is that the growing the grain temperature of third step is 6-8 DEG C.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110713470A (en) * | 2019-11-02 | 2020-01-21 | 迪嘉药业集团有限公司 | Flunarizine hydrochloride crystal form B and preparation method thereof |
| CN117064863A (en) * | 2023-08-02 | 2023-11-17 | 贵州缔谊健康制药有限公司 | Preparation method of flunarizine hydrochloride capsules |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20080200474A1 (en) * | 2007-02-15 | 2008-08-21 | Transform Pharmaceuticals, Inc. | Novel flunarizine salt forms and methods of making and using the same |
| CN105998024A (en) * | 2016-06-15 | 2016-10-12 | 迪沙药业集团有限公司 | Flunarizine-hydrochloride pharmaceutical composition |
-
2019
- 2019-08-30 CN CN201910820519.7A patent/CN110467586B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20080200474A1 (en) * | 2007-02-15 | 2008-08-21 | Transform Pharmaceuticals, Inc. | Novel flunarizine salt forms and methods of making and using the same |
| CN105998024A (en) * | 2016-06-15 | 2016-10-12 | 迪沙药业集团有限公司 | Flunarizine-hydrochloride pharmaceutical composition |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110713470A (en) * | 2019-11-02 | 2020-01-21 | 迪嘉药业集团有限公司 | Flunarizine hydrochloride crystal form B and preparation method thereof |
| CN110713470B (en) * | 2019-11-02 | 2022-01-18 | 迪嘉药业集团有限公司 | Flunarizine hydrochloride crystal form B and preparation method thereof |
| CN117064863A (en) * | 2023-08-02 | 2023-11-17 | 贵州缔谊健康制药有限公司 | Preparation method of flunarizine hydrochloride capsules |
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